We aspire to streamline the translation of genetic and genomic technologies and knowledge among rare diseases with unmet therapeutic needs. We apply genome engineering technology to dissect pathogenetic mechanisms and develop innovative therapeutic approaches for rare neuromuscular & neurological diseases.

LAMA2-deficient Congenital Muscular Dystrophy  (LAMA2-CMD)

LAMA2 protein stabilizes the basement membrane and maintains muscle architecture and nerve myelination. LAMA2-CMD patients have mutations in the LAMA2 gene, leading to muscle degeneration and neuropathy. Despite considerable advances in our understanding of the pathophysiology of LAMA2-CMD, currently, there is no curative option. 

 

Our goal is to develop a mutation-independent approach for LAMA2-CMD by upregulating a disease modifier gene LAMA1 to compensate for the lack of LAMA2. 

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We show that postnatal Lama1 upregulation, achieved using CRISPR activation and delivered via Adeno-associated viral vector 9 (AAV9), can ameliorate dystrophic phenotypes in a mouse model of LAMA2-CMD (Kemaladewi, Bassi et al, Nature, 2019). We are currently building on this technology and focusing on: 

Aim 1: Evaluation of a novel miniaturized CRISPR activation system to upregulate Lama1 in LAMA2-CMD mouse model

We assess the efficacy of Lama1 upregulation on survival, neuromuscular, respiratory functions, and safety parameters in LAMA2-CMD mice following therapeutic interventions.

Aim 1

Aim 2: Interrogation of the compensatory mechanism of human LAMA1 in LAMA2-CMD patient cells

 

We evaluate the rescue of mitochondrial bioenergetic, migration properties, and myelination in patient-derived cellular models following LAMA1 upregulation. 

Aim 2

Snyder-Robinson Syndrome (SRS): Inborn Error of Polyamine Metabolism

We have previously found that altered polyamine metabolism contributes to the skeletal muscle pathophysiology in congenital muscular dystrophy (Kemaladewi et al, Human Molecular Genetics, 2018). 

 

Interestingly, patients with Snyder-Robinson Syndrome, an X-linked recessive neurological disorder caused by mutations in Spermine Synthase, a key player in polyamine metabolism, have a history of being misdiagnosed as congenital myopathy. In addition, patients have impaired neurological functions and skeletal abnormalities. 

Polyamines

Using a combination of a novel mouse model, a variety of cutting-edge in vivo imaging and genetic tools, we focus on: 

Aim 1: Interrogation of the role of polyamines in neurological and musculoskeletal functions

Aim 2: Development of therapeutic genome editing strategy in Snyder-Robinson Syndrome